Low Levels of miR-218 Impact Motor Neuron Function

In a new direction for amyotrophic lateral sclerosis (ALS) research that looks at incremental biological changes around a critical threshold, scientists from the Salk Institute conducted a systematic review of past studies that profiled microRNA levels in patients with ALS. They found that miR-218 kept showing up as being lower, but not completely lost, in people with ALS. 

Using a mouse model of ALS, the team devised a strategy to finely lower the levels of miR-218 in a controlled way to study the effects on motor neurons’ control of muscle function. They found that there’s a critical threshold somewhere between 36 percent and 7 percent of normal levels that leads to muscle paralysis and death. Above 36 percent, neuromuscular junctions are normal and healthy; below 7 percent, neuromuscular deficits are lethal. The rest of the study was focused on trying to understand why that was the case.

It turns out that miR-218 regulates the function of about 300 different genes. Many of them encode proteins related to how motor neurons grow axons and send signals to muscle. Once the levels of miR-218 dropped below 36 percent, the way these neurons could signal to muscles dropped off dramatically. The researchers used cutting-edge tools in the lab to determine how miR-218 was influencing various genes.

“Instead of acting like a simple switch, the molecule miR-218 is like an orchestra conductor of 300 musicians playing together,” explains Neal Amin, first author of the paper published today in Neuron. “Instead of gradually telling all of the players to dim the volume of their instruments in unison, it’s telling some musicians to play more quietly and others to stop completely. It has a much more dynamic and complex control over gene function than we ever previously appreciated.”

The researchers say that being able to study this fine-tuning in animal models will allow them to learn much more about how genetic mutations that reduce gene expression put patients at risk for developing brain disorders. This could eventually lead to new treatments that get at the heart of the biological changes that lead to disease. The research not only has implications for ALS, but for other diseases of the nervous system, including schizophrenia, which has also been associated with changes in the expression level of microRNAs.